Consistent with the aims of the IRCSSA, this R01 application will examine whether noradrenergic agents, shown to be effective in improving stress-induced decrements in self-control (see Project 2: PI - Arnsten) and to attenuate stress-induced reinstatement to drug use with pre-clinical models, will attenuate the ability of stress to precipitate smoking lapse behavior in humans. Several lines of evidence identify that stress is a primary mechanism involved in smoking relapse. Despite this knowledge, targeting stress-related relapse as a viable medications development strategy for nicotine dependence has not yet been explored. For the current proposal, we are planning to continue with the development of a novel self-administration paradigm to examine how stress facilitates lapse behavior for the purpose of medication screening. The first occurrence of smoking during a cessation attempt is a critical transition, and represents an important target for medication development. Our lapse model is focused on two primary aspects of early lapse behavior: 1) ability to resist the first cigarette, representing a laboratory marker of self-control and 2) subsequent smoking. We have several ongoing studies utilizing this smoking-lapse model to examine various precipitants of relapse (stress, nicotine deprivation, food deprivation, alcohol, cigarette availability) and are currently using these models to examine effects of medications hypothesized to influence the models' primes (R21DA017234; P50AA015632; P50DA013334). Use of such laboratory-based paradigms provides a means to efficiently and cost-effectively screen new therapeutics, and to translate pre-clinical findings generated by IRCSSA Projects 2 to 5, to relapse behavior in humans. The primary aim of STUDY 1 will be to finalize the parameters of the Stress-Lapse Model, which will model the effect of stress + nicotine deprivation + cigarette availability on the inability to resist smoking in daily smokers. Secondarily, we will examine potential mechanisms underlying stress-precipitated smoking lapse behavior including self-control, craving, mood, cardiovascular reactivity, stress-related neuroendocrine measures, neuropeptides, and endocannabinoids. For STUDY 2 (Guanfacine, an alpha-2 adrenergic receptor agonist) and STUDY 3 (Carvedilol, an alpha-1 and beta adrenergic blocker), we will use the Stress- Lapse Model to examine whether noradrenergic agents attenuate the ability of stress to precipitate smoking lapse behavior, and will explore potential mechanisms for medication effects. Results will provide important evidence that targeting stress-related relapse is a viable medications development strategy for nicotine dependence, and will provide the impetus to expand this investigation to other addictive disorders.